CAG repeat expansion in autosomal dominant familial spastic paraparesis: novel expansion in a subset of patients

Autosomal dominant familial spastic paraplegia (FSP) is a geneticallyheterogeneous neurodegenerative disorder displaying anticipation for whichthree loci have been mapped to the chromosomal positions 14q11.2- q24.3(SPG3), 2p21-p24 (SPG4) and 15q11.1 (SPG6). The repeat expansion detection(RED) method has been used to demonstrate expanded CAG repeats in some FSPfamilies that map to SPG4. We analyzed 20 FSP families, including four forwhich there is evidence for linkage to SPG4, and found that in most casesthe repeat expansion detected by RED is due to non-pathogenic expansions ofthe chromosome 18q21.1 SEF2-1 or 17q21.3 ERDA1 locus. Polymorphicexpansions at SEF2-1 and ERDA1 appear frequent and may confound RED studiesin the search for genes causing disorders demonstrating anticipation. Insix FSP families, however, CAG repeat expansion was detected in a subset ofaffected and at-risk individuals that did not result from expansion of theSEF2-1 and ERDA1 loci. Overall, 11 of 37 (30%) of the FSP patients with aCAG/CTG repeat expansion are unaccounted for by the SEF2-1 and ERDA1 loci,compared with two of 23 (9%) of the unaffected at-risk individuals and noneof 19 controls. In the majority of cases these novel expansions wereshorter than those previously reported.